For several decades nitroglycerin has been administered to humans as a vasodilating agent in the treatment of cardiovascular disease. In about 1987, it was shown that nitroglycerin so administered is converted in the body to nitric oxide which is the pharmacologically active metabolite. Still more recently, nitric oxide has been shown to be formed in endothelial cells from arginine as a normal metabolite which is an important endothelium-derived relaxing factor (EDRF). It is now widely accepted that many naturally occurring substances which act as physiological vasodilators mediate all or part of their action by stimulating release of EDRF; these substances include acetylcholine, histamine, bradykinin, leukotrienes, ADP, ATF, substance P, serotonin, thrombin and others. EDRF is currently being intensively studied as participating in regulation of blood flow and vascular resistance. Incident to such study, a search has been carried out for compounds which inhibit nitric oxide production in the body. One compound discovered for use to obtain this effect is the arginine antagonist N.sup.G -methyl-L-arginine (Sakuma, I., et al, Proc. Natl. Acad. Sci. USA 85, 8664-8667 (1988)). Administration of N.sup.G -methyl-L-arginine to guinea pigs and rabbits has been shown to increase blood pressure (Aisaka, K., et al, Biochemical and Biophysic Research Communications, Vol. 160, No. 2, pp. 881-886, 4/28/89; Rees, D. D., et al, Proc. Natl. Acad. Sci. USA, Vol. 86, pp. 3375-3378, 5/89). Recently, it has been discovered that arginine antagonists inhibit systemic hypotension (Kilbourn, R. G. et al. U.S. Pat. No. 5,028,627) and that very effective arginine antagonists are physiologically active N.sup.G -amino-L-arginine (Griffith, O. W. U.S. Pat. No. 5,059,712) and physiologically active N.sup.G -(hydrazinoiminomethyl)lysine (Griffith, O. W., U.S. Pat. No. 5,132,453). It has also been discovered that the duration of the nitric oxide-mediated hypotensive response to acetylcholine is prolonged in animals infused with L-arginine (Aiaska, K., et al, Biochem. Biophys. Res. Commun. 163, 710-717, 1989).
In addition to vascular endothelium, macrophages have also been shown to produce nitric oxide in the body which is a component of their cell killing and/or cytostatic function (Iyengar, R., et al, Proc. Natl. Acad. Sci, USA, Vol. 84, pp. 6369-6373, 9/87). It has also been shown that addition of arginase to macrophage cell culture medium prevents the activated macrophage cytoxic effector mechanism (Hibbs, J. B., et al, The Journal of Immunology, Vol. 138, No. 2, 550-565, 1/87).
It is thought that in sepsis or cytokine-induced shock, induced production of nitric oxide plays an important role in the observed life-threatening hypotension and is a basis for the clinically observed insensitivity to pressor agents such as .alpha..sub.1 adrenergic agonists used in the treatment of said hypotension. Very recently it has been discovered that administration of nitric oxide synthesis inhibitors in combination with .alpha..sub.1 adrenergic agonists in the treatment of said hypotension, potentiates the action of the .alpha..sub.1 adrenergic agonists by restoring vascular sensitivity to effects of said agonists. (Gross, S. S., et al, U.S. Pat. No. 5,216,025).